Estradiol regulates leptin sensitivity to control feeding via hypothalamic Cited1.
Cell Metab. 2023 Mar 7;35(3):438-455.e7. doi: 10.1016/j.cmet.2023.02.004. PMID: 36889283.
|Authors/Editors:||González-García I, García-Clavé E, Cebrian-Serrano A, Le Thuc O, Contreras RE, Xu Y, Gruber T, Schriever SC, Legutko B, Lintelmann J, Adamski J, Wurst W, Müller TD, Woods SC, Pfluger PT, Tschöp MH, Fisette A, García-Cáceres C.|
Until menopause, women have a lower propensity to develop metabolic diseases than men, suggestive of a
protective role for sex hormones. Although a functional synergy between central actions of estrogens and
leptin has been demonstrated to protect against metabolic disturbances, the underlying cellular and molec-
ular mechanisms mediating this crosstalk have remained elusive. By using a series of embryonic, adult-
onset, and tissue/cell-specific loss-of-function mouse models, we document an unprecedented role of
hypothalamic Cbp/P300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 1 (Cited1) in
mediating estradiol (E2)-dependent leptin actions that control feeding specifically in pro-opiomelanocortin
(Pomc) neurons. We reveal that within arcuate Pomc neurons, Cited1 drives leptin’s anorectic effects by
acting as a co-factor converging E2 and leptin signaling via direct Cited1-ERa-Stat3 interactions. Together,
these results provide new insights on how melanocortin neurons integrate endocrine inputs from gonadal
and adipose axes via Cited1, thereby contributing to the sexual dimorphism in diet-induced obesity.